The three-dimensional structure of a series of "variable surface glycoprotein" (VSG) antigens from the membrane of the unicellular parasite, Trypanosoma brucei, are being determined by high resolution X- ray crystallography. The African trypanosome evades the host immune response by sequentially expressing antigenically distinct VSGs, which form a protective coat on its surface. Just as the host responds to one foreign antigenic challenge, the trypanosome expresses a new antigenically distinct VSG, escaping neutralization by the host. Our goal is to understand the structure of this remarkable series of surface glycoproteins and their role in antigenic variation. African trypanosomes, which are spread by the tsetse fly, cause various forms of animal and human trypanosomiasis (sleeping sickness). These studies aim to describe the structure of the VSG protein and carbohydrate, the location and nature of the antigenic determinants, and should provide a molecular model of the VSG, which can be used for the rational design of drugs and/or vaccines. Currently, the structures of the variable N-Terminal domain of MITat 1.2 and ILTat 1.25 VSGs are being determined to 2.9 and 2.5A resolution respectively from crystals of the purified glycoproteins. Future studies on complexes with monoclonal antibody Fab fragments and on electron microscopic image analysis of the VSG coat are proposed.